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The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function.

ABSTRACT: Haploinsufficiency of Progranulin (PGRN), a gene encoding a secreted glycoprotein, is a major cause of frontotemporal lobar degeneration with ubiquitin (FTLD-U) positive inclusions. Single nucleotide polymorphisms in the TMEM106B gene were recently discovered as a risk factor for FTLD-U, especially in patients with PGRN mutations. TMEM106B is also associated with cognitive impairment in amyotrophic lateral sclerosis patients. Despite these studies, little is known about TMEM106B at molecular and cellular levels and how TMEM106B contributes to FTLD. Here, we show that TMEM106B is localized in the late endosome/lysosome compartments and TMEM106B levels are regulated by lysosomal activities. Ectopic expression of TMEM106B induces morphologic changes of lysosome compartments and delays the degradation of endocytic cargoes by the endolysosomal pathway. Furthermore, overexpression of TMEM106B correlates with elevated levels of PGRN, possibly by attenuating lysosomal degradation of PGRN. These results shed light on the cellular functions of TMEM106B and the roles of TMEM106B in the pathogenesis of FTLD-U with PGRN mutations.

SUBMITTER: Brady OA

PROVIDER: S-EPMC3554197 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function.

Brady Owen A OA Zheng Yanqiu Y Murphy Kira K Huang Marshall M Hu Fenghua F

Human molecular genetics 20121106 4

Haploinsufficiency of Progranulin (PGRN), a gene encoding a secreted glycoprotein, is a major cause of frontotemporal lobar degeneration with ubiquitin (FTLD-U) positive inclusions. Single nucleotide polymorphisms in the TMEM106B gene were recently discovered as a risk factor for FTLD-U, especially in patients with PGRN mutations. TMEM106B is also associated with cognitive impairment in amyotrophic lateral sclerosis patients. Despite these studies, little is known about TMEM106B at molecular and ...[more]

PMID: 23136129

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Project description:BackgroundFrontotemporal lobar degeneration (FTLD) is the second most common cause of dementia in individuals under 65 years old and manifests as alterations in behavior, personality, or language secondary to degeneration of the frontal and/or temporal lobes. FTLD-TDP, the largest neuropathological subset of FTLD, is characterized by hyperphosphorylated, ubiquitinated TAR DNA-binding protein 43 (TDP-43) inclusions. Mutations in progranulin (GRN), a neuroprotective growth factor, are one of the most common Mendelian genetic causes of FTLD-TDP. Moreover, a recent genome-wide association study (GWAS) identified multiple SNPs within the uncharacterized gene TMEM106B that significantly associated with FTLD-TDP, suggesting that TMEM106B genotype confers risk for FTLD-TDP. Indeed, TMEM106B expression levels, which correlate with TMEM106B genotype, may play a role in the pathogenesis of disease.ResultsSince little is known about TMEM106B and its expression in human brain, we performed immunohistochemical studies of TMEM106B in postmortem human brain samples from normal individuals, FTLD-TDP individuals with and without GRN mutations, and individuals with other neurodegenerative diseases. We find that TMEM106B protein is cytoplasmically expressed in both histopathologically affected and unaffected areas of the brain by neurons, glia, and endothelial cells/pericytes. Furthermore, we demonstrate that TMEM106B expression may differ among neuronal subtypes. Finally, we show that TMEM106B neuronal expression is significantly more disorganized in FTLD-TDP cases with GRN mutations, compared to normal and disease controls, including FTLD-TDP cases without GRN mutations.ConclusionsOur data provide an initial neuropathological characterization of the newly discovered FTLD-TDP-associated protein TMEM106B. In addition, we demonstrate that FTLD-TDP cases with GRN mutations exhibit a loss of neuronal TMEM106B subcellular localization, adding to evidence that TMEM106B and progranulin may be pathophysiologically linked in FTLD-TDP.

Dataset Information

The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function.

Publications

The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function.

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